Reactive oxygen species cause cell and tissue damage, presumably through the chemical modifications of critical structural and functional biological molecules. The bipyridylium compound diquat causes hepatic necrosis in vivo by mechanisms that appear to be mediated by the metabolic redox cycling generation of reactive oxygen species, and thus is a useful model of diseases in which oxidant stress mechanisms are proposed. A dose of 0.1 mmol/kg of diquat reliably causes hepatic necrosis in male F344 rats, but in the present studies we found that female F344 rats showed no liver damage, as indicated by elevations in plasma transaminase (ALT) activities, at doses less than 0.2 mmol/kg. Hepatic glutathione concentrations were not different in female than in male F344 rats and were not altered significantly by doses of diquat that did not alter plasma ALT activities. Decreases in GSH levels were observed after doses of diquat that increased plasma ALT activities, but appear to reflect secondary effects of injury rather than a contributing mechanism. Hepatic GSSG levels were not increased in the rats studied 6 h after administration of diquat. Glutathione peroxidase, glutathione transferase, and glutathione reductase activities were increased in female rats at doses of diquat above 0.1 mmol/kg. By western analyses of fractions treated with 2,4-dinitrophenylhydrazine, hepatic proteins in diquat-treated female rats appeared to be more highly oxidized than were proteins in male rats, even at comparable levels of hepatic damage, with some notable differences in the specific proteins oxidized. The identities of these proteins are not known, but such studies might provide useful insights into the mechanisms of injury and resistance. Increases in biliary efflux of GSSG was diquat dose-dependent in both male and female rats and greater in males than in females, per given dose. However, biliary GSSG efflux in females given 0.15 mmol/kg of diquat was equal to the efflux observed in males given 0.1 mmol/kg, so the greater resistance of females to diquat-induced hepatic necrosis is not readily explained as simply greater rates of generation of reactive oxygen species, but suggests some other mechanism(s) of resistance to oxidant stresses that are greater in females.